ER Coregulators in Prostate

ERs are ligand-dependent transcription factors which bind to the ERE to regulate the transcription of target genes. The transcription initiation is a complex process which involves the cooperative interaction between ERs and multiple factors at the promoter region of target genes. The occurrence of transcriptional interference between nuclear receptors in early transient receptor/reporter co-transfection assays suggested the existence of common rate limiting cofactors, other than general transcription factors (GTFs), required for ERs activation function.35,36 In this regard, coregulators were identified, and defined as coactivators or corepressors required for transcriptional regulation.37 In this chapter, we will mainly focus on the expression pattern of some identified ER coactivators in the prostate tissue and prostate cancer cell lines.

To date, there are numerous ER coregulators that have been identified and the most well characterized ER coactivators belong to the p160 family, including SRC-1, SRC-2 (TIF2/GRIP1) and SRC-3 (AIB1/RAC3).37 Among these identified ER coactivators, SRC-3/RAC3/AIB1 is the most well studied in prostate cancer cell lines. Using Western blotting, Gnanapragasam et al. showed that SRC3/RAC3/AIB1 protein has the highest expression in LNCaP cells, moderate expression in PC-3 cells, and low-level expression in DU145 cells.38 In the human prostate tissue, the levels of SRC-3/RAC3/AIB1 expression is significantly correlated with tumor grade and stage of disease, but not with serum PSA levels.38 SRC-1 is expressed as a major RNA transcript of 7.5 kb in many tissues, including prostate. The expression levels of SRC-1 were found to be elevated in the cancer specimens with a higher grade or poor response to endocrine therapy, than in those with a lower grade or good response to endocrine therapy.39 In addition to SRC-1 and SRC-3, other ER co-regulators, CBP/p300, SMRT, and N-CoR, are also expressed in prostate.40

Overall, most of ER co-regulators identified to date are not specific to ER, and can interact with other nuclear receptors, including AR.41 Therefore, how these co-regulators regulate ER function in prostate development and neoplastic transformation remains to be elucidated. In addition, whether any ER specific associated proteins exist in prostate needs further investigation.

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